Various drugs such as alkylating agents, metabolism antagonists, antitumor antibiotics and platinum compounds have been used in the past for chemotherapy on human tumors. In the case where remarkable therapeutic effects are not observed when these antitumor agents are used alone, therapeutic methods have been devised in which a plurality of antitumor agents are used concomitantly (Frei, E. III, Cancer Res., 32, 2593-2607, 1992). Tumor cells exhibit various sensitivities to antitumor agents, and certain cells are known to exhibit resistance to therapy by antitumor agents (Magrath, I., New Directions in Cancer Treatment, 1989, Springer-Verlag). Acquisition of resistance to therapy by tumor cells is said to be caused by, for example, the occurrence of multi-drug resistance (MDR) (Tsuruo, T. et al., Cancer Res., 42, 4730-4733, 1982), reduction in cell uptake of antitumor agent (Sherman, S. E. et al., Science, 230, 412, 1985), increased DNA repair activity (Borch, R. F., Metabolism and Action of Anticancer Drugs, Powis, G. & Prough, R. ed., Taylor & Francis, London, 1987, 163-193), or promotion of inactivation of antitumor agent in the cells (Teicher, B. A. et al., Cancer Res., 46, 4379, 1986). In such cases, there are many cases in which the expected therapeutic effects are not observed simply by administering antitumor agent.
Renal cell carcinoma exhibits resistance to therapy to antitumor agents such as cisplatin, adriamycin and vinblastine (Kakehi, Y. et al., J. Urol., 139, 862-864, 1988; Kanamaru, H. et al., J. Natl. Cancer Inst., 81, 844-847, 1989; Teicher, B. A. et al., Cancer Res., 47, 388-393, 1987). Platinum compounds such as cisplatin that possess antitumor effects bond with DNA and inhibit DNA synthesis and cell division (Pinto, A. L. et al., Biochica et Biophysica Acta, 780, 167-180, 1985).
The expression of glutathione-S transferase-.pi. (GST-.pi.), inhibition of the effects of cisplatin caused by an increase in intracellular levels of substances containing sulfidryl groups, increased DNA repair activities, or activation of oncogenes such as c-myc is considered to be involved in the resistance to therapy of renal cell carcinoma to cisplatin (Sklar, M. D. et al., Cancer Res., 51, 2118-2123, 1991; Mizutani, Y. et al., Cancer in press, 1994; Nakagawa, K. et al., Japan J. Cancer Res., 79, 301-305, 1988).
In addition, changes in membrane permeability and transport capabilities in tumor cells are said to cause a decrease in cisplatin uptake within the cells, thus increasing resistance to therapy to cisplatin (Richon, V. et al., Cancer Res., 47, 2056-2061, 1987; Waud, W. R. et al., Cancer Res., 47, 6549-6555, 1987). Glutathione, an example of a substance containing sulfidryl groups that is present in the largest amounts in mammalian animal cells, is reported to inactivate cisplatin in cells, and certain types of tumors have been shown to have higher intracellular glutathione and metallothionein levels (Hromas, R. A. et al., Cancer LETT., 34, 9-13, 1987; Taylor, D. M. et al., Eur. J. Cancer, 12, 249-254, 1976).
Glutathione is a tripeptide thiol. It plays an important role in the inactivation of DNA-bonding substances such as alkylating agents and cisplatin and in the repair of cell damage caused by these. One of the effects of GST-.pi. is that it promotes inactivation of antitumor agents by causing antitumor agents like those described above to bond to glutathione.
Since renal cell carcinoma produces interleukin-6 (IL-6) and expresses IL-6 receptor (IL-6R), it has been suggested that IL-6 plays some type of role in the growth activity of renal cell carcinoma (Miki, S. et al. FEBS Lett., 250, 607-610, 1989; Takenawa, J. et al., J. Natl. Cancer. Inst., 83, 1668-1672, 1991). Moreover, it has been reported that the level of IL-6 in the serum increases when the prognosis for treatment of renal cell carcinoma patients is poor (Blay, J. et al., Cancer Res., 52, 3317-3322, 1992; Tsukamoto, T. et al., J. Urol., 148, 1778-1782, 1992). However, a clear correlation between IL-6 and the resistance to therapy of renal cell carcinoma to antitumor agents has not yet been found, and is still unknown.
IL-6 is a multi-functional cytokine referred to as B cell stimulating factor-2 or Interferon .beta.2. IL-6 was discovered as a differentiation factor involved in the activation of B lymphoid cells (Hirano, T. et al., Nature, 324, 73-76, 1986). Later, it was clearly shown to be a multi-functional cytokine that affects the functions of various cells (Akira, S. et al., Adv. in Immunology, 54, 1-78, 1993). IL-6 transmits its biological activity by means of two proteins present on cells.
One of them is IL-6R, a ligand bonding protein having a molecular weight of approximately 80 KD to which IL-6 bonds. In addition to the cell bonding form which is expressed on the cell membrane by passing through the cell membrane, it is also present as soluble IL-6R (sIL-6R), which is mainly composed of its extracellular region. Another protein is gp130 having a molecular weight of approximately 130 KD that is involved in signal transmission of non-ligand bonding. IL-6 and IL-6R form an IL-6/IL-6R complex. As a result of then bonding with the other membrane protein gp130, the biological activity of IL-6 is transmitted to the cell (Taga, et al., J. Exp. Med., 196, 967, 1987).
Although platinum compounds like cisplatin and antitumor agents such as mitomycin C induce apoptosis in tumor cells, IL-6 has been reported to inhibit apoptosis induced by antitumor agents (Kerr, J. et al., Cancer, 73, 2013-2026, 1994; Sachs, L. et al., Blood, 82, 15-21, 1993). In addition, antitumor agents like cisplatin and mitomycin C have cytotoxic effects on tumor cells as a result of producing free radicals (Oyanagi, Y. et al., Biochem. Pharmacol., 26, 473-476, 1997; Nakano, H. et al., Biochem. Biophys. Acta., 796, 285-293, 1984). IL-6, however, is known to promote the expression of manganese superoxide dismutase (MnSOD), which has the effect of decomposing free radicals, and IL-6 antibody inhibits the expression of this promoted MnSOD (Ono, M. et al., Biochem. Biophys. Res. Commun., 182, 1100-1107, 1992; Dougall, W. C. et al., Endocrinology, 129, 2376-2384, 1991).
However, none of these reports state that the effects of antitumor agents are enhanced by blocking the biological activity of IL-6. In addition, there are no reports of actually attempting to use an IL-6 antagonist as an effect enhancer of antitumor agents.
Although antitumor agents have been used in the treatment of tumors in the past, since large doses of these drugs produce adverse side effects such as nausea, vomiting, kidney and liver function disorders and inhibition of bone marrow function, there have been cases in which it was dangerous to administer the required dose of antitumor agent for adequately demonstrating antitumor effects. In addition, since there are tumors having resistance to therapy in which chemotherapy using ordinary antitumor agents is not effective, there is a need for an effect enhancer that increases the sensitivity of these tumors to antitumor agents.
The object of the present invention is to provide a novel antitumor agent effect enhancer that assists and enhances the effects of antitumor agents and increases the sensitivity of therapy-resistant tumor cells to antitumor agents. More specifically, the present invention provides an antitumor agent effect enhancer comprising IL-6 antagonist. More specifically, the present invention provides a chemotherapeutic agent effect enhancer having antitumor effects, comprising IL-6 antagonist.